The connective tissues of mammals are constantly subjected to stresses and strains from mechanical forces that can result in afflictions, such as arthritis, joint inflammation and stiffness. Such afflictions are especially acute in joints, such as the neck, back, arms, hips, ankles and feet. Indeed, connective tissue afflictions are quite common, presently affecting millions of Americans. Further, such afflictions cannot only be painful but, in their extreme, can also be debilitory.
The treatment of connective tissue afflictions can be quite problematic. A simple decrease in the stress to which the connective tissue is subjected is often not usually an option, especially in the case of athletes and mammals such as race horses. Thus, an interruption in the traumatic pathways can often not be achieved. Consequently, especially in the case of athletes, humans and animals, treatment is often directed at controlling the symptoms of the afflictions and not their causes, regardless of the stage of the degenerative process.
Presently, steroids, such as corticosteroids, and other anti-inflammatory materials, such as NSAIDS, high doses of aspirin are widely used for the treatment of these ailments; Pharmocol. Res. Commun. 10 557-569 (1978) by Vidal et al. In addition, hyaluronic acid and polysulfated glycosaminoglycan is used in veterinary medicine, especially for equines. While these materials often relieve the pain and swelling associated with maladies arising from connective tissue problems, almost all drugs eventually wear out their effectiveness. Furthermore, drugs may also inhibit the body's own natural healing processes, leading to further deterioration of the connective tissue.
The connective tissues are naturally equipped to repair themselves by manufacturing and remodeling prodigious amounts of collagen (a chief component of connective tissues) and proteoglycans (PG's)--the other major component of connective tissues. This ongoing process is placed under stress when an injury occurs to connective tissues. In such cases, the production of connective tissue (along with collagen and proteoglycans) can double or triple over normal amounts, thereby increasing the demand for the building blocks of both collagens and proteoglycans.
The building blocks for collagen are amino acids, especially proline, glycine and lysine. Proteoglycans (PG's) are large and complex macromolecules comprised mainly of long chains of modified sugars called glycosaminoglycans (GAG's) or mucopolysaccharides. PG's provide the framework for collagen to follow. They also hold water to give the connective tissues (especially cartilage) flexibility, resiliency and resistance to compression.
Like almost every biosynthetic pathway in the body, the pathways by which both collagen and GAG form single molecule precursors, are quite long. As is also characteristic of other biosynthetic pathways, the pathways by which collagen and GAG's are produced include what is called a rate-limiting step--that is, one highly regulated control point beyond which there is a commitment to finish. The presence of such rate-limiting steps permit such complicated processes to be more easily and efficiently controlled by permitting the organism to focus on one point. For example, if conditions demand production and all the requisite raw materials are in place, then stimulation of the rate-limiting step will cause the end product to be produced. To stop or slow production, then the organism needs simply to regulate the rate-limiting step.
In the production of collagen, the rate-limiting step is the maturation, rather than the production, of newly synthesized collagen. Unused collagen is simply degraded back to amino acids. Proteoglycans, however, have a specific rate-limiting step in their production.
In the production of PG's, the rate-limiting step is the conversion of glucose to glucosamine for the production of GAG's. Glucosamine is the key precursor to all the various modified sugars found in GAG's--glucosamine sulfate, galactosamine, N-acetylglucosamine, etc. Glucosamine also makes up 50% of hyaluronic acid--the backbone of PG's--on which other GAG's, like chondroitin sulfates are added. The GAG's are then used to build PG's and, eventually, connective tissue. Once glucosamine is formed, there is no turning away from, the synthesis of GAG polymers and the synthesis of collagen.
There are several disclosures of which we are aware wherein it has been suggested to bypass the rate-limiting step of the conversion of glucose to glucosamine in those pathways that produce proteoglycans by the provision of exogenous quantities of glucosamine. For example, the intravenous administration of glucosamine (a precursor of the GAG's) and derivations thereof have been disclosed in U.S. Pat. No. 3,232,836 issued to Carlozzi et al, for assisting in the healing of wounds on the surface of the body. In U.S. Pat. No. 3,682,076 issued to Rovati, the use of glucosamine and salts thereof are disclosed for the treatment of arthritic conditions. Finally, the use of glucosamine salts has also been disclosed for the treatment of inflammatory diseases of the gastrointestinal tract in U.S. Pat. No. 4,006,224 issued to Prudden.
There have also been several disclosures of which we are aware wherein it has been suggested to go one step further in bypassing the rate-limiting step, by providing excess quantities of various of the modified sugars found in the GAG's for producing proteoglycans. For example, in U.S. Pat. No. 3,6797,652 issued to Rovati et al, the use of N-acetylglucosamine is disclosed for treating degenerative afflictions of the joints.
In still other disclosures of which we are aware, it has been taught to go still one step further in bypassing the glucose to glucosamine rate-limiting step by providing excess quantities of the GAG's themselves (with and without various of the modified sugars). For example, in U.S. Pat. No. 3,371,012 issued to Furuhashi, a preservative is disclosed for eye graft material that includes galactose, N-acetylglucosamine (a modified sugar found in the GAG's) and chondroitin sulfate (a GAG). Additionally, U.S. Pat. No. 4,486,416 issued to Soll et al, discloses a method of protecting corneal endothelial cells exposed to the trauma of intraocular lens implantation surgery by administering a prophylactically effective amount of chondroitin sulfate. Also, U.S. Pat. No. 5,141,928 issued to Goldman discloses the prevention and treatment of eye injuries using glycosaminoglycan polysulfates.
U.S. Pat. No. 4,983,580 issued to Gibson, discloses methods for enhancing healing of corneal incisions. These methods include the application of a corneal motor composition of fibronectin, chondroitin sulfate and collagen to the incision.
Finally, in U.S. Pat. No. 4,801,619 issued to Lindblad, the intraarticular administration of hyaluronic acid is disclosed for the treatment of progressive cartilage degeneration caused by proteoglycan degradation.
While the above references have, to varying degrees, been useful for their intended purposes, none have proven entirely satisfactory. In particular, the absorption rates of the various compositions disclosed have not been entirely satisfactory nor have their ability to increase GAG production. In addition, none of the compositions are provided with both the glucosamine starting material in conjunction with a GAG (such as chondroitin sulfate). Finally, none of the disclosured compositions include any catalysts which facilitate the production of PG's from its various building blocks.
Accordingly, it can be seen that there remains a need for a therapeutic composition which include glucosamine, GAG's and catalysts for aiding in the conversion of these materials to protoglycans for facilitating the repair of connective tissue in mammals.